EP0654473B1 - Cyclopropane derivatives and antiviral agents containing the same - Google Patents

Cyclopropane derivatives and antiviral agents containing the same Download PDF

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Publication number
EP0654473B1
EP0654473B1 EP94308492A EP94308492A EP0654473B1 EP 0654473 B1 EP0654473 B1 EP 0654473B1 EP 94308492 A EP94308492 A EP 94308492A EP 94308492 A EP94308492 A EP 94308492A EP 0654473 B1 EP0654473 B1 EP 0654473B1
Authority
EP
European Patent Office
Prior art keywords
compound
group
cyclopropan
methylguanine
bis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP94308492A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0654473A1 (en
Inventor
Takaaki c/o Central Res. Lab. Sekiyama
Osamu c/o Central Res. Lab. Ikemura
Tomoyuki c/o Central Res. Lab. Onishi
Takashi C/O Central Res. Lab. Tsuji
Satoshi c/o Central Res. Lab. Iwayama
Katsuya c/o Central Res. Lab. Suzuki
Yuko c/o Central Res. Lab. Ohmura
Masahiko C/O Central Res. Lab. Okunishi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ajinomoto Co Inc
Original Assignee
Ajinomoto Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ajinomoto Co Inc filed Critical Ajinomoto Co Inc
Publication of EP0654473A1 publication Critical patent/EP0654473A1/en
Application granted granted Critical
Publication of EP0654473B1 publication Critical patent/EP0654473B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to cyclopropane derivatives having an antiviral activity which are useful as an agent for treating various viral diseases, and also relates to an antiviral agent containing the same.
  • nucleic acid derivatives have antiviral activity, and acyclovir, ganciclovir, azidothymidine, etc. have been practically used as an antiviral agent.
  • these nucleic acid derivatives have problems since they generally have poor solubility in water. For example, in order to use as an injection, these compounds should be dissolved in a large amount of water and administered by the intravenous drip. Moreover, these compounds can hardly be used as an ophthalmic solution.
  • Japanese patent application JP-A-59/10587 discloses amino acid esters of acyclovir, particularly, glycine or alanine esters of acyclovir, as a compound having an improved solubility in water as compared with acyclovir.
  • Unexamined published Japanese patent application No. 64-68373 discloses that valine and isoleucine esters of acyclovir have better bioavailability (oral absorbability) after oral administration in comparison with the glycine and alanine esters.
  • Japanese patent application JP-A-2/218667 discloses amino acid esters of ganciclovir, but does not include oral absorbability data. Accordingly, it is not clear what type of amino acid esters could improve oral absorbability.
  • Japanese patent application JP-A-5/78357 discloses that the compound represented by the following general formula (II) has potent antiviral activity.
  • X represents a hydrogen atom, a hydroxyl group, an amino group, or a halogen atom
  • Y represents a hydrogen atom, a hydroxyl group, or an amino group.
  • this compound also has low solubility in water and has problems such as poor oral absorbability and poor transdermal permeability.
  • the present inventors have conducted extensive studies on the compound represented by the general formula (II) above to improve solubility in water and oral absorbability and, as a result, found that the oral absorbability may be improved and the treatment effect enhanced by esterifying the hydroxyl group of this compound with certain amino acids.
  • the present invention relates to a cyclopropane derivative represented by the general formula (I): wherein R 1 and R 2 , both represent a group represented by the formula (1): in which X represents a hydrogen atom, a hydroxyl group, an amino group, or a halogen atom; and Y represents a hydrogen atom, a hydroxyl group, or an amino group, or a pharmaceutically acceptable salt thereof, as well as an antiviral agent comprising the same.
  • R 1 and R 2 both represent a group represented by the formula (1): in which X represents a hydrogen atom, a hydroxyl group, an amino group, or a halogen atom; and Y represents a hydrogen atom, a hydroxyl group, or an amino group, or a pharmaceutically acceptable salt thereof, as well as an antiviral agent comprising the same.
  • the configuration of the compound of the general formula (1) due to the asymmetric carbon atom is S-configuration.
  • halogen atom examples include fluorine, chlorine, bromine and iodine.
  • Examples of the pharmaceutically acceptable salt include salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and with organic acid such as acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, succinic acid, and methanesulfonic acid.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid
  • organic acid such as acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, succinic acid, and methanesulfonic acid.
  • the cyclopropane derivative of the present invention may be a single stereoisomer, or may be a mixture of stereoisomers, for instance a racemic mixture of optically active isomers.
  • the relative configuration of the each compound is represented by the symbols ⁇ and ⁇ , where ⁇ means the group at the lower side position of the cyclopropane plane and ⁇ means the group at the upper side position of cyclopropane plane.
  • R 1 and R 2 are both groups of formula (1) can be prepared by, for example, the following process. wherein X, and Y, are as defined above, R 3 is methyl and Z represents a protective group for an amino group.
  • a cyclopropane derivative (the formula (1)) prepared by the method as described in EP-A-502690 (JP-A-5/78357), etc. and an N-protected amino acid (the formula (2)) are subjected to coupling in a polar solvent such as dimethylformamide, pyridine, acetonitrile, and tetrahydrofuran, using a coupling agent such as carbodiimides (e.g., N,N'-dicyclohexylcarbodiimide) and 2-chloro-1-methylpyridinium tosylate to obtain an ester of the formula (3).
  • a coupling agent such as carbodiimides (e.g., N,N'-dicyclohexylcarbodiimide) and 2-chloro-1-methylpyridinium tosylate.
  • the amino-protective group in the ester obtained was removed by an appropriate way to obtain the object compound (the formula (4)).
  • amino-protective group in the formula (2) those generally used for the peptide synthesis can be used for the present invention and examples thereof include a t-butoxycarbonyl group, a benzyloxycarbonyl group, etc.
  • the protective group can be removed by making the condition acidic using trifluoroacetic acid, hydrochloric acid, etc.
  • a benzyloxycarbonyl group the protective group can be removed by catalytic hydrogenation in the presence of palladium-carbon.
  • an azido group can also be used as a protective group, which can be converted to an amino group by reduction.
  • the reaction can be carried out by using active esters of the N-protected amino acid with N-hydroxysuccinimide, 2,4-dinitrophenol, etc. or acid anhydrides of the N-protected amino acid can be used.
  • the compound of the present invention has antiviral activity and expected to be useful as an antiviral agent.
  • the virus include herpes simplex virus, cytomegalovirus, varicella-zoster virus, Epstein-Barr virus, and hepatitis viruses.
  • the compound of the present invention is used as an antiviral agent by intravenous administration, oral administration, transdermal administration, or ophthalmic administration. Although clinical dose may vary depending on the symptoms and age of the patient, route of administration, and the like, the dose is generally from 0.1 to 500 mg/kg/day.
  • the compound of the present invention is administered as an antiviral composition prepared by mixing the compound with an appropriate pharmaceutical carrier.
  • Examples of the dosage form of the preparation include injections, tablets, granules, fine granules, powders, capsules, creams, suppositories.
  • Examples of the pharmaceutical carrier include lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, carboxymethylcellulose calcium, magnesium stearate, talc, acetylated cellulose, sucrose, titanium oxide, benzoic acid, parahydroxybenzoates, sodium dehydroacetate, acacia, tragacanth, methylcellulose, egg yolk, surfactants, simple syrup, citric acid, distilled water, glycerin, propylene glycol, macrogols, sodium monohydrogenphosphate, sodium dihydrogenphosphate, sodium phosphate, sodium chloride, phenol, Salomethyl, and sodium hydrogensulfite.
  • the content of the active ingredient according to the present invention in the preparation may vary depending on the dosage form of the preparation and should not particularly be limited, but the active ingredient is generally used in an amount of 0.01 to 80% by weight, preferably 1 to 70% by weight, based on the total amount of the preparation.
  • test compounds were dissolved in 0.2 ml of physiological saline and orally administered to 5-week-age male ICR mouse in a dose of 0.1 mmol/kg. After 15 minutes, 30 minutes, 1 hour, 2 hours, or 4 hours from the administration, blood was collected from three mice, respectively, and centrifuged at 3,000 rpm for 10 minutes to obtain a plasma. A 20 % trichloroacetic acid aqueous solution (100 ⁇ l) was added to the plasma (100 ⁇ l) and the resulting mixture was shaken and then centrifuged at 8,000 rpm for 1 minutes to obtain a supernatant.
  • Test Compound AUC ( ⁇ M ⁇ hr) Compound of Example 1 49 Compound of Comparative Example 1 14 Compound of Comparative Example 2 12 Compound of Comparative Example 3 14 Compound of Comparative Example 4 10 Compound of Comparative Example 5 0 Compound of Comparative Example 6 1 Compound of Comparative Example 7 6 Compound of Comparative Example 8 22 Compound of Comparative Example 9 20 Compound of Comparative Example 10 25 9-[1'S,2'R-bis(hydroxymethyl) cyclopropan-1'-yl]methylguanine 16 9-(2-O-L-valyloxyethoxy)methylguanine 40
  • the compound of the present invention has superior oral absorbability to 9-[1'S,2'R-bis(hydroxymethyl)cyclopropan-1'-yl]methylguanine, which is the equivalent or more excellent oral absorbability in comparison with 9-(2-O-L-valyloxyethoxy)methylguanine.
  • a 4-week-age male CDF-1 mouse was intraperitoneally infected with HSV-1 (Tomioka strain) in an amount of 2.4 ⁇ 10 5 pfu/mouse. Three hours after the infection, administration of each test compound was started. The test compound was dissolved in 0.2 ml of distilled water for injection use and intragastrically administered via catheter once a day for 5 days in a dose of 0.625, 1.25, or 2.5 ⁇ mol/kg/day. Each of the test groups consisted of 10 mice, and the survival ratio after 21 days from the administration and the average survival days were obtained. The results are shown in the following Table 2.
  • one of the compounds of the present invention i.e. 9-[1'S,2'R-bis(O-L-alanyloxymethyl)cyclopropan-1'-yl]methylguanine, has superior efficacy to 9-[1'S,2'R-bis(hydroxymethyl)cyclopropan-1'-yl]methylguanine.
  • the cyclopropane derivatives of the present invention are excellent in solubility in water and can provide antiviral agents excellent in oral absorbability and treatment effect.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Virology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)
EP94308492A 1993-11-18 1994-11-17 Cyclopropane derivatives and antiviral agents containing the same Expired - Lifetime EP0654473B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP28902093 1993-11-18
JP28902093 1993-11-18
JP289020/93 1993-11-18

Publications (2)

Publication Number Publication Date
EP0654473A1 EP0654473A1 (en) 1995-05-24
EP0654473B1 true EP0654473B1 (en) 1999-09-08

Family

ID=17737794

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94308492A Expired - Lifetime EP0654473B1 (en) 1993-11-18 1994-11-17 Cyclopropane derivatives and antiviral agents containing the same

Country Status (10)

Country Link
EP (1) EP0654473B1 (enrdf_load_stackoverflow)
KR (1) KR950014110A (enrdf_load_stackoverflow)
CN (1) CN1041729C (enrdf_load_stackoverflow)
AT (1) ATE184282T1 (enrdf_load_stackoverflow)
CA (1) CA2136159A1 (enrdf_load_stackoverflow)
DE (1) DE69420514T2 (enrdf_load_stackoverflow)
DK (1) DK0654473T3 (enrdf_load_stackoverflow)
ES (1) ES2138052T3 (enrdf_load_stackoverflow)
GR (1) GR3031767T3 (enrdf_load_stackoverflow)
TW (1) TW282470B (enrdf_load_stackoverflow)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6703394B2 (en) 1996-02-16 2004-03-09 Medivir Ab Acyclic nucleoside derivatives
US5869493A (en) * 1996-02-16 1999-02-09 Medivir Ab Acyclic nucleoside derivatives
WO1999032490A1 (en) * 1997-12-19 1999-07-01 Bristol-Myers Squibb Company Prodrugs of lobucavir and methods of use
JP3709793B2 (ja) * 2001-01-29 2005-10-26 株式会社村田製作所 振動ジャイロおよびそれを用いた電子装置および振動ジャイロの自己診断方法
JP2004026695A (ja) * 2002-06-24 2004-01-29 M's Science Corp 水性点眼用製剤
GB0814065D0 (en) * 2008-08-01 2008-09-10 Univ Leuven Kath Use of nucleoside analogs as anti-koi herpes virus molecules

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL8202626A (nl) * 1982-06-29 1984-01-16 Stichting Rega V Z W Derivaten van 9-(2-hydroxyethoxymethyl)guanine.
US4617304A (en) * 1984-04-10 1986-10-14 Merck & Co., Inc. Purine derivatives
US4859680A (en) * 1984-04-10 1989-08-22 Merck & Co., Inc. Pyrimidine derivatives as antiviral compounds
AP55A (en) * 1987-08-15 1989-09-26 The Wellcome Foundation Ltd Therapeutic Acyclic Nucleosides
EP0375329B1 (en) * 1988-12-19 1995-05-31 The Wellcome Foundation Limited Antiviral pyrimidine and purine compounds, process for their preparation and pharmaceutical compositions containing them
AU647822B2 (en) * 1990-09-14 1994-03-31 Marion Merrell Dow Inc. Novel carbocyclic adenosine analogs useful as immunosuppressants
ES2139588T3 (es) * 1991-03-05 2000-02-16 Ajinomoto Kk Derivado de ciclopropano.
JPH0680670A (ja) * 1992-09-03 1994-03-22 Ajinomoto Co Inc シクロプロパン誘導体及びその製造法

Also Published As

Publication number Publication date
CA2136159A1 (en) 1995-05-19
KR950014110A (ko) 1995-06-15
TW282470B (enrdf_load_stackoverflow) 1996-08-01
DE69420514T2 (de) 2000-05-18
EP0654473A1 (en) 1995-05-24
ATE184282T1 (de) 1999-09-15
DE69420514D1 (de) 1999-10-14
GR3031767T3 (en) 2000-02-29
ES2138052T3 (es) 2000-01-01
CN1041729C (zh) 1999-01-20
CN1111244A (zh) 1995-11-08
DK0654473T3 (da) 2000-03-20

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